Curable calcium phosphate compositions for use with porous structures and methods of using the same

ABSTRACT

Various embodiments disclosed relate to curable calcium phosphate compositions for use with porous structures and methods of using the same. In various embodiments, the present invention provides a curable calcium phosphate composition or a cured product thereof, with the curable calcium phosphate composition including calcium phosphate and a perfusion modifier. In various embodiments, the present invention provides an apparatus comprising a porous structure at least partially in contact with the curable calcium phosphate composition or a cured product thereof. The porous structure can include a porous substrate including a plurality of ligaments that define pores of the porous substrate, and a biocompatible metal coating on the plurality of ligaments of the porous substrate.

CLAIM OF PRIORITY

This application is a divisional of U.S. patent application Ser. No.15/288,149, filed Oct. 7, 2016, which claims the benefit of U.S.Provisional Patent Application Ser. No. 62/238,776, filed on Oct. 8,2015, the benefit of priority of each of which is claimed hereby, andeach of which is incorporated by reference herein in its entirety.

BACKGROUND

Healthy trabecular or cancellous human bone has interconnected pores inthe range of 100-600 microns in diameter and has a compressive strengthof nominally 0.5-10 MPa. The structure of trabecular bone has animportant role in the tolerance of skeletal tissue to mechanicalstresses. Typical methods for implantation of orthopedic devices thatmimic the biomechanical properties of trabecular bone leave regions ofthe remaining host bone not contacted to or interfaced with theorthopedic device, decreasing the security and rigidity with which theimplant is seated in the remaining host bone, slowing healing andosteo-incorporation into the implant, and increasing the likelihood ofrevision surgery.

SUMMARY OF THE INVENTION

In various embodiments, the present invention provides a curable calciumphosphate composition. The curable calcium phosphate compositionincludes calcium phosphate and a perfusion modifier. In someembodiments, the present invention provides a cured product of thecurable calcium phosphate composition, In some embodiments, the presentinvention provides a method including using the curable calciumphosphate composition or a cured product thereof for treatment of ajoint disorder or condition.

In various embodiments, the present invention provides an apparatus. Theapparatus includes a porous structure at least partially in contact witha curable calcium phosphate composition or a cured product thereof, withthe curable calcium phosphate composition including calcium phosphateand a perfusion modifier. In some embodiments, the present inventionprovides a method of making the apparatus. The method of making theapparatus can include placing the curable calcium phosphate compositionat least partially in contact with the porous structure to form theapparatus. In some embodiments, the present invention provides a methodincluding using the apparatus for treatment of a joint disorder orcondition.

In some embodiments, the porous structure includes a porous substrateincluding a plurality of ligaments that define pores of the poroussubstrate. In some embodiments, the porous substrate can includereticulated vitreous carbon foam. The porous structure can also includea biocompatible metal coating on the plurality of ligaments of theporous substrate. In some embodiments, the biocompatible metal coatingcan include tantalum metal.

Various embodiments of the present invention provide certain advantagesover other compositions, apparatuses, and methods of using the same, atleast some of which are unexpected. For example, in various embodiments,the composition, apparatus, and method of using the same can provideincreased contact between the host bone and an orthopedic implant. Insome embodiments, by providing increased contact between the host boneand the implant, the composition, apparatus, and method of using thesame can provide a more rigid and secure connection between the hostbone and the implant (e.g., decreasing the chance of implant loosening).In some embodiments, by providing increased contact between the hostbone and the implant, the composition, apparatus, and method of usingthe same can provide increased healing speed, increased speed ofosteo-incorporation into the implant, and increased extent ofosteo-incorporation into the implant. In some embodiments, by providingincreased contact between the host bone and the implant, thecomposition, apparatus, and method of using the same can provide adecreased chance that revision surgery will be needed, or can increasethe time span between implantation and revision surgery.

In various embodiments, the curable calcium phosphate composition can bea reactive precursor to a bone-remodelable solid (e.g., the curedproduct of the curable calcium phosphate composition). As used herein,“bone-remodelable” refers to a process including resorption of thematerial (e.g., removal) followed by ossification (e.g., new boneformation). In various embodiments, the cured product of the curablecalcium phosphate composition can be more bone-remodelable than othercompositions, such as other bone substitute materials, remodeling morequickly, more completely, or a combination thereof. In variousembodiments (e.g., prior to hydration), the curable calcium phosphatecomposition can provide a stable intermediate for production of areactive precursor to a bone-remodelable solid. In various embodiments,the stable intermediate can be more stable, can be stored for longerperiods, or a combination thereof, as compared to other compositions forforming bone-rem odelable solids. In various embodiments, the curablecalcium phosphate composition can provide more controlled andpredictable crystallization kinetics (e.g., to form the cured product ofthe composition) than other compositions. In various embodiments, thecurable composition can provide reduced or no phase separation betweenreactive solids and carrier fluid during use. In various embodiments,the curable composition can provide reduced or no phase separation orpremature crystallization of the cured product of the composition duringuse, as compared to other compositions that form bone-remodelablematerials.

In various embodiments, the curable calcium phosphate composition canenhance the biomechanical properties and eventual integration of aporous structure into bone. In various embodiments, the curable calciumphosphate composition can be used in contact with a porous structure toincrease integration of new bone with porous surfaces of the porousstructure. In various embodiments, the cured product of the curablecalcium phosphate composition can provide a bone-remodelable conductivescaffold for integration of new bone with the surface of the porousstructure. In various embodiments, the cured product of the curablecalcium phosphate composition can form an uninterrupted or lessinterrupted conductive interface with the surrounding host bone andaugment the porous structure. In various embodiments, the curablecalcium phosphate composition can have a flowability and viscosity thatis suitable for injecting not only around a porous structure but also atleast partially within the porous structure (e.g., perfused within). Invarious embodiments, the curable calcium phosphate composition can atleast partially be used inside the porous structure, causing increasedspeed and extent of bone interdigitation within the porous structureduring the recovery process.

In various embodiments, the method of using the curable calciumphosphate composition, the cured product thereof, or the method of usingor forming the apparatus including the porous structure and the curablecomposition or a cured product thereof, can be compatible with minimallyinvasive surgical techniques. In various embodiments, the curablecalcium phosphate composition can accelerate osseous integration, suchas of the porous structure, such as via osteoconductivity of the curedproduct thereof. In various embodiments, the curable calcium phosphatecomposition can be conveniently injected with nominal digital (i.e.,finger) pressure. In various embodiments, augmentation of implants withthe curable calcium phosphate composition can enhance bone ingrowth andend-to-end fusion (e.g., with an ankle fusion implant).

BRIEF DESCRIPTION OF THE FIGURES

The drawings are not necessarily drawn to scale. The drawings illustrategenerally, by way of example, but not by way of limitation, variousembodiments discussed in the present document.

FIG. 1 illustrates an implanted apparatus including a curable calciumphosphate composition and a porous structure, in accordance with variousembodiments.

FIGS. 2A-B illustrate an implanted apparatus including a curable calciumphosphate composition and a porous structure, in accordance with variousembodiments.

FIG. 3 illustrates an implanted apparatus including a curable calciumphosphate composition and a porous structure, in accordance with variousembodiments.

FIG. 4 illustrates an implanted apparatus including a curable calciumphosphate composition and a porous structure, in accordance with variousembodiments.

FIGS. 5A-D illustrate various views of a porous metal block, inaccordance with various embodiments.

FIG. 6 illustrates an extrusion testing set up, in accordance withvarious embodiments.

FIGS. 7A-B illustrate penetration of a bone substitute material througha porous metal block, in accordance with various embodiments.

DETAILED DESCRIPTION OF THE INVENTION

Reference will now be made in detail to certain embodiments of thedisclosed subject matter, examples of which are illustrated in part inthe accompanying drawings. While the disclosed subject matter will bedescribed in conjunction with the enumerated claims, it will beunderstood that the exemplified subject matter is not intended to limitthe claims to the disclosed subject matter.

Throughout this document, values expressed in a range format should beinterpreted in a flexible manner to include not only the numericalvalues explicitly recited as the limits of the range, but also toinclude all the individual numerical values or sub-ranges encompassedwithin that range as if each numerical value and sub-range is explicitlyrecited. For example, a range of “about 0.1% to about 5%” or “about 0.1%to 5%” should be interpreted to include not just about 0.1% to about 5%,but also the individual values (e.g., 1%, 2%, 3%, and 4%) and thesub-ranges (e.g., 0.1% to 0.5%, 1.1% to 2.2%, 3.3% to 4.4%) within theindicated range. The statement “about X to Y” has the same meaning as“about X to about Y,” unless indicated otherwise. Likewise, thestatement “about X, Y, or about Z” has the same meaning as “about X,about Y, or about Z,” unless indicated otherwise.

In this document, the terms “a,” “an,” or “the” are used to include oneor more than one unless the context clearly dictates otherwise. The term“or” is used to refer to a nonexclusive “or” unless otherwise indicated.The statement “at least one of A and. B” has the same meaning as “A, B,or A and B.” In addition, it is to be understood that the phraseology orterminology employed herein, and not otherwise defined, is for thepurpose of description only and not of limitation. Any use of sectionheadings is intended to aid reading of the document and is not to beinterpreted as limiting; information that is relevant to a sectionheading may occur within or outside of that particular section. Allpublications, patents, and patent documents referred to in this documentare incorporated by reference herein in their entirety, as thoughindividually incorporated by reference. In the event of inconsistentusages between this document and those documents so incorporated byreference, the usage in the incorporated reference should be consideredsupplementary to that of this document; for irreconcilableinconsistencies, the usage in this document controls.

In the methods described herein, the acts can be carried out in anyorder without departing from the principles of the invention, exceptwhen a temporal or operational sequence is explicitly recited.Furthermore, specified acts can be carried out concurrently unlessexplicit claim language recites that they be carried out separately. Forexample, a claimed act of doing X and a claimed act of doing Y can beconducted simultaneously within a single operation, and the resultingprocess will fall within the literal scope of the claimed process.

The term “about” as used herein can allow for a degree of variability ina value or range, for example, within 10%, within 5%, or within 1% of astated value or of a stated limit of a range, and includes the exactstated value or range.

The term “substantially” as used herein refers to a majority of, ormostly, as in at least about 50%, 60%, 70%, 80%, 90%, 9.5%, 96%, 97%,98%,, 99%, 99.5%, 99.9%, 99.99%, or at least about 99.999% or more, or100%.

As used herein, the term “polymer” refers to a molecule having at leastone repeating unit and can include copolymers.

In various embodiments, salts having a positively charged counterion caninclude any suitable positively charged counterion. For example, thecounterion can be ammonium(NH₄ ⁺), or an alkali metal such as sodium(Na⁺), potassium (K⁺), or lithium (Li⁺). In some embodiments, thecounterion can have a positive charge greater than +1, which can in someembodiments complex to multiple ionized groups, such as Zn²⁺, Al³⁺, oralkaline earth metals such as Ca²⁺ or Mg²⁺.

In various embodiments, salts having a negatively' charged counterioncan include any suitable negatively charged counterion. For example, thecounterion can be a halide, such as fluoride, chloride, iodide, orbromide. In other examples, the counterion can be nitrate, hydrogensulfate, dihydrogen phosphate, bicarbonate, nitrite, perchlorate,iodate, chlorate, bromate, chlorite, hypochlorite, hypobromite, cyanide,amide, cyanate, hydroxide, permanganate. The counterion can be aconjugate base of any carboxylic acid, such as acetate or formate. Insome embodiments, a counterion can have a negative charge greater than-1, which can in some embodiments complex to multiple ionized groups,such as oxide, sulfide, nitride, arsenate, phosphate, arsenite, hydrogenphosphate, sulfate, thiosulfate, sulfite, carbonate, chromate,dichromate, peroxide, or oxalate.

The polymers described herein can terminate in any suitable way. In someembodiments, the polymers can terminate with an end group that isindependently chosen from a suitable polymerization initiator, —H, —OH,a substituted or unsubstituted (C₁-C₂₀)hydrocarbyl (e.g., (C₁-C₁₀)alkylor (C₆-C₂₀)aryl) interrupted with 0, 1, 2, or 3 groups independentlyselected from —O—, substituted or unsubstituted —NH—, and —S—, apoly(substituted or unsubstituted (C₁-C₂₀)hydrocarbyloxy), and apoly(substituted or unsubstituted (C₁-C₂₀)hydrocarbylamino).

Curable Calcium Phosphate Composition, or Cured Product Thereof

In various embodiments, the present invention provides a curable calciumphosphate composition. The curable calcium phosphate compositionincludes calcium phosphate and a perfusion modifier. The curable calciumphosphate composition, in an unhydrated state, can be in the form of apowder, such as a flowable powder. In a hydrated state, the curablecalcium phosphate composition can be in the form of a flowable paste orputty having a consistency and viscosity that is suitable for perfusioninto and around a porous structure, and that can be suitable forinjection through a needle. In a hydrated state, the curable calciumphosphate composition can be moldable and cohesive when applied to animplant site in vivo. The curable calcium phosphate composition, in ahydrated state, can cure (e.g., harden) to form a. cured product of thecurable calcium phosphate composition. The curable calcium phosphatecomposition can be self-curable, such that in a hydrated state, thecomposition cures to form a solid material without using any curingaccelerators and without exposing the curable composition to particularconditions for curing.

The cured product can have a different composition than the curablecalcium phosphate composition (e.g., during curing, reaction products ofthe curable composition can form that are different than the componentsof the curable composition). The cured product of the calcium phosphatecomposition can approximate the chemical composition of natural bone.The cured product of the calcium phosphate composition can includecalcium phosphate (e.g., any one or more materials that qualify as acalcium phosphate, and not necessarily the same one or more materialsthat were present in the curable composition). The cured product of thecalcium phosphate composition can be suitable as a bone-substitutematerial, can be used to repair bone (e.g., damaged bone), can bebone-remodelable, and can be sufficiently strong and rigid to providestructural support to the surrounding regions of a host bone. The curedproduct of the calcium phosphate composition can be used as a deliveryvehicle for biologically active materials (e.g., wherein thebiologically active materials can be present in the curable composition,or can be added to the cured product after formation thereof). The curedproduct of the calcium phosphate composition can be formed outside apatient and then implanted, or the curable composition can be implantedin a patient and then allowed to cure in vivo.

The curable calcium phosphate composition can be in an unhydrated state(e.g., a powder) or a hydrated state (e.g., a paste). When the curablecalcium phosphate is in a hydrated state, at least some aqueous fluid ispresent in the curable calcium phosphate composition, such as water orsaline. The amount of fluid in the composition can be adjusted toprovide a desired. consistency of the hydrated curable calcium phosphatecomposition (e.g., more or less viscous). The aqueous fluid can be about0.001 wt % to about 99.999 wt % of the composition, about 30 wt % toabout 60 wt %, about 40 wt % to about 50 wt %; or about 0.001 wt % orless, or less than, equal to, or more than 0.01 wt %, 0.1, 1, 2, 3, 4,5, 6, 8, 10, 12, 14, 16, 18, 20, 25, 30, 32, 34, 36, 38, 40, 41, 42, 43,44, 45, 46, 47, 48, 49, 50, 52, 54, 56, 58, 60, 65, 70, 75, 80, 82, 84,86, 88, 90, 91, 92, 93, 94. 95, 96, 97, 98, 99, 99.9, 99.99 wt %, orabout 99.999 wt % or more. The aqueous fluid can include aphysiologically acceptable fluid. The physiologically acceptable fluidcan include or can be water, saline, phosphate buffer, biological fluid,or a combination thereof. The biological fluid can include or can beblood (e.g., whole blood, warm or cold blood, and stored or fresh blood;treated blood, such as blood diluted with at least one physiologicalsolution, including but not limited to saline, nutrient, oranticoagulant solutions, or a combination thereof), a blood component(e.g., platelet concentrate (PC), apheresed platelets, platelet-richplasma (PRP), platelet-poor plasma (PPP), platelet-free plasma, plasma,serum, fresh frozen plasma (FFP), components obtained from plasma,packed red cells (PRC), buffy coat (BC), or a combination thereof), ablood product (e.g., blood products derived from blood or derived frombone marrow), milk, urine, saliva, seminal fluid, vaginal fluid,synovial fluid, lymph fluid, amniotic fluid, the fluid within a yolk sacof an egg, chorion of an egg, allantois of an egg, sweat, tears, or acombination thereof.

The calcium phosphate can be any one or more minerals that include atleast one calcium ion (Ca²⁺) and a phosphate, such as an orthophosphate(PO₄ ³⁻), metaphosphate (PO₃ ¹⁻), a pyrophosphate (P₂O₇ ⁴⁻). The calciumphosphate can include a hydrogen or hydroxide ion. The calcium phosphatecan include one calcium phosphate mineral or more than one calciumphosphate mineral. The calcium phosphate (e.g., the one or more calciumphosphate minerals) can form any suitable proportion of the curablecalcium phosphate composition, such as about 0.001 wt % to about 99.999wt % of the composition, about 40 wt % to about 99.999 wt %, about 40 wt% to about 70 wt %, or about 40 wt % to about 60 wt %, or about 0.001 wt% or less, or less than, equal to, or more than about 0.01 wt %, 0.1, 1,2, 3, 4, 5, 6, 8, 10, 12, 14, 16, 18, 20, 25, 30, 32, 34, 36, 38, 40,41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58,59, 60, 62, 64, 66, 68, 70, 75, 80, 82, 84, 86, 88, 90, 91, 92, 93, 94,95, 96, 97, 98, 99. 99.9, 99.99 wt %, or about 99.999 wt % or more. Thecalcium phosphate can include amorphous calcium phosphate, poorlycrystalline calcium phosphate, hydroxyapatite, carbonated apatite (e.g.,calcium-deficient hydroxyapatite), monocalcium phosphate, calciummetaphosphate, heptacalcium phosphate, dicalcium phosphate dihydrate,tetracalcium phosphate, octacalcium phosphate, calcium pyrophosphate,tricalcium phosphate, or a combination thereof. As used herein andapplied to a calcium phosphate, the term “amorphous” means a calciumphosphate having no or only short range crystallographic order, e.g.,crystallographic order over less than 100 nm. The calcium phosphate caninclude amorphous calcium phosphate and a second calcium phosphateincluding poorly crystalline calcium phosphate, hydroxyapatite,carbonated apatite (e.g., calcium-deficient hydroxyapatite), monocalciumphosphate, calcium metaphosphate, heptacalcium phosphate, dicalciumphosphate dihydrate, tetracalcium phosphate, octacalcium phosphate,calcium pyrophosphate, tricalcium phosphate, or a combination thereof.The calcium phosphate can include or can be a combination of amorphouscalcium phosphate and dicalcium phosphate dihydrate, wherein the massratio of the amorphous calcium phosphate to the dicalcium phosphatedihydrate can be about 99:1 or more, or less than, equal to, or morethan 19:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1, 1:1, 1:2, 1:3, 1:4,1:5, 1:6, 1:7, 1:8, 1:9, 1:19, or about 1:99 or less.

The perfusion modifier can be any one or more perfusion modifiercompounds that, when included in the curable calcium phosphatecomposition of the invention, improve the ability of the calciumphosphate composition to infiltrate the porous network of a porousstructure (e.g., at least the parts of the porous network at and nearthe surface of the porous structure), such as a porous network similarto a trabecular network of cancellous bone. The perfusion modifier(e.g., the one or more perfusion modifier compounds) can be any suitableproportion of the curable calcium phosphate composition, such as about0.001 wt % to about 50 wt % of the composition, about 0,001 wt % toabout 20 wt %, about 0.5 wt % to about 10 wt %, or about 0.001 wt % orless, or less than, equal to, or more than about 0.01 wt %, 0.1, 0.5, 1,1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12, 14, 16, 18, 20, 25, 30,35, 40, 45 wt %, or about 50 wt % or more of the composition. Theperfusion modifier can include or can be one or more polymers. Theperfusion modifier can include or can be a polysaccharide, a nucleicacid, a carbohydrate, a protein, a polypeptide, a poly(α-hydroxy acid),a poly(lactone), a poly(amino acid), a poly(anhydride), apoly(orthoester), a poly(anhydride-co-imide), a poly(orthocarbonate), apoly(α-hydroxy alkanoate), a poly(dioxanone), a poly(phosphoester),sodium alginate, alginic acid, arabic gum, guar gum, xantham gum,gelatin, chitin, chitosan, chitosan acetate, chitosan lactate,chondroitin sulfate, N,O-carboxymethyl chitosan, a dextran (e.g.,α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, or sodium dextransulfate), fibrin glue, glycerol, hyaluronic acid, sodium hyaluronate, acellulose methylcellulose, carboxymethylcellulose,hydroxypropylmethylcellulose, hydroxyethylcellulose, a salt thereof, ora combination thereof), a glucosamine, a proteoglycan, a starch (e.g.,starch or a starch derivative such as hydroxyethyl starch), lactic acid,a poly(ethylene oxide-co-propylene oxide) (e.g., Plutonic® series),sodium glycerophosphate, collagen, glycogen, a keratin, silk,poly(L-lactide) (PLLA), poly(D,L-lactide) (PDLLA), polyglycolide (PGA),poly(lactide-co-glycolide) (PLGA), poly(L-lactide-co-D, L-lactide),poly(D,L-lactide-co-trimethylene carbonate), polyhydroxybutyrate (PHB),poly(ϵ-caprolactone), poly(δ-valerolactone), poly(γ-butyrolactone),poly(caprolactone), polyacrylic acid, polycarboxylic acid,poly(allylamine hydrochloride), poly(diallyldimethylammonium chloride),poly(ethyleneimine), polypropylene fumarate, polyvinyl alcohol,polyvinylpyrrolidone, polyethylene, polymethylmethacrylate, carbonfibers, poly(ethylene glycol), poly(ethylene oxide), poly(vinylalcohol), poly(vinylpyrrolidone), poly(ethyloxazoline), poly(ethyleneoxide)-co-poly(propylene oxide) block copolymers, poly(ethyleneterephthalate)polyamide, copolymers thereof, or a combination thereof.In some embodiments, the perfusion modifier can be a cellulose orcellulose derivative, such as carboxymethylcellulose. The perfusionmodifier can be a lyophilized perfusion modifier, wherein one or morecompounds in the perfusion modifier are lyophilized. For example, theperfusion modifier can be a calcium carboxymethylcellulose sponge orfibers lyophilized from a dilute basic aqueous solution of a calciumsalt and sodium carboxymethylcellulose. Calcium ions can be exchangedand sequestered as a carboxylate salt, available to precipitate insolution with phosphates, available to quench anticoagulants such asACD-A, or available to initiate platelet activation and clotting. Thus,the curable composition can include a lyophilized perfusion modifierstabilized by sequestration of ionic elements and ligands.

In some embodiments, the curable calcium phosphate composition includesa biologically active modifier. In some embodiments, the curable calciumphosphate composition is free of biologically active modifiers. Thecurable calcium phosphate composition can include one biologicallyactive modifier or multiple biologically active modifiers. The one ormore biologically active modifiers can form any suitable proportion ofthe curable calcium phosphate composition, such as about 0.001 wt % toabout 40 wt % of the composition, about 0.001 wt % to about 10 wt %, orabout 0.001 wt % or less, or less than, equal to, or more than about0.01 wt %, 0.1, 1, 2., 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, 20, 22,24, 26, 28, 30, 32, 34, 36, 38, or about 40 wt % or more of thecomposition. The biologically activate modifier can be at least one ofan antibody, an antibiotic, a polynucleotide, a polypeptide, a protein(e.g., an osteogenic protein, such as BMP-2, BMP-3, BMP-3b, BMP-4,BMP-5, BMP-6, BMP-7, BMP-8, BMP-9, BMP-10, BMP-11, BMP-12, BMP-13,BMP-14, BMP-15, BMP-16, BMP-17, BMP-18, or a combination thereof), ananti-cancer modifier, a growth factor, a vaccine, or a combinationthereof. Anti-cancer modifiers can include alkylating modifiers,platinum modifiers, antimetabolites, topoisomerase inhibitors, antitumorantibiotics, antimitotic modifiers, aromatase inhibitors, thymidylatesynthase inhibitors, DNA antagonists, farnesyltransferase inhibitors,pump inhibitors, histone acetyltransferase inhibitors, metalloproteinaseinhibitors, ribonucleoside reductase inhibitors, TNF alpha agonists, TNFalpha antagonists, endothelin A receptor antagonists, retinoic acidreceptor agonists, immuno-modulators, hormonal modifiers, antihormonalmodifiers, photodynamic modifiers, and tyrosine kinase inhibitors.

In various embodiments, the curable calcium phosphate compositionincludes a binder. In some embodiments, the curable calcium phosphatecomposition is free of binders. The curable calcium phosphatecomposition can include one binder or more than one binder. The one ormore binders can form any suitable proportion of the curable calciumphosphate composition, such as about 0.001 wt % to about 20 wt % of thecomposition, about 0.001 wt % to about 5 wt %, or about 0.001 wt % orless, or less than, equal to, or more than about 0.01 wt %, 0.1, 1, 2,3, 4, 5, 7, 8, 9, 10, 12, 14, 16, 18 wt %, or about 20 wt % or more. Thebinder can be at least one of a) a polysaccharide, a nucleic acid, acarbohydrate, a protein, a polypeptide, a poly(α-hydroxy acids), apoly(lactone), a poly(amino acid), a poly(anhydride), apoly(orthoester), a poly(anhydride-co-imide), a poly(orthocarbonate), apoly(α-hydroxy alkanoate), a poly(dioxanone), a poly(phosphoester),poly(L-lactide) (PHA), poly(D,L-lactide) (PDLLA), polyglycolide (PGA),poly(lactide-co-glycolide (PLGA), poly(L-lactide-co-D, L-lactide),poly(D,L-lactide-co-trimethylene carbonate), polyhydroxybutyrate (MB),poly(ϵ-caprolactone), poly(δ-valerolactone), poly(γ-butyrolactone),poly(caprolactone), polyacrylic acid, polycarboxylic acid,poly(allylamine hydrochloride), poly(diallyldimethylammonium chloride),poly(ethyleneimine), polypropylene fumarate, polyvinyl alcohol,polyvinylpyrrolidone, a polyethylene, polymethylmethacrylate, a carbonfiber, poly(ethylene glycol), poly(ethylene oxide), poly(vinyl alcohol),poly(vinylpyrrolidone), poly(ethyloxazoline), a poly(ethyleneoxide)-co-poly(propylene oxide) block copolymer, poly(ethyleneterephthalate)polyamide, and copolymers thereof; b) a homo- orco-polymer having one or more monomers selected from the groupconsisting of acrolein potassium, (meth)acrylamides, (meth)acrylic acidand salts thereof, (meth)acrylates, acrylonitrile, ethylene, ethyleneglycol, ethyleneimine, ethyleneoxide, styrene sulfonate, vinyl acetate,vinyl alcohol, vinyl chloride, and vinylpyrrolidone); c) a polyphenolcomplexing agent selected from a gallotannin, a ellagitannin, ataragallotannin, a caffetannin, a proanthocyanidin, catechin,epicatechin, chlorogenic acid, and arbutin; and d) an agent selectedfrom alginic acid, arabic gum, guar gum, xanthan gum, gelatin, chitin,chitosan, chitosan acetate, chitosan lactate, chondroitin sulfate,N,O-carboxymethyl chitosan, a dextran (e.g., α-cyclodextrin,β-cyclodextrin, γ-cyclodextrin, or sodium dextran sulfate), fibrin glue,glycerol, hyaluronic add, sodium hyaluronate, a cellulose (e.g.,methylcellulose, carboxymethylcellulose, hydroxypropylmethylcellulose,hydroxyethylcellulose, a salt thereof, or a combination thereof), aglucosamine, a proteoglycan, a starch, lactic acid, a poly(ethyleneoxide-co-propylene oxide), sodium glycerophosphate, collagen, glycogen,a keratin, and silk.

In various embodiments, the curable calcium phosphate compositionincludes an effervescent agent. In some embodiments, the curable calciumphosphate composition is free of an effervescent agent. The curablecalcium phosphate composition can include one effervescent agent ormultiple effervescent agents. The one or more effervescent agents canform any suitable proportion of the curable calcium phosphatecomposition, such as about 0.001 wt % to about 40 wt % of thecomposition, or about 0.001 wt % or less, or less than, equal to, ormore than about 0.01 wt %, 0.1, 1, 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, 18,20, 22, 24, 26, 28, 30, 32, 34, 36, 38, or about 40 wt % or more. Insome embodiments, the effervescent agent includes a combination of atleast two compounds. The effervescent agent can include a carbonatecompound and a bicarbonate compound which can react to form CO₂ gas uponhydration (or soon thereafter) of said composition. The carbonate andbicarbonate compounds can have a molar ratio of about about 1:9, orabout 1:1 or less, or less than, equal to, or more than about 1:2, 1:3,1:4, 1:5, 1:6, 1:7, 1:8, or about 1:9 or more. The carbonate andbicarbonate compounds can have any suitable counterion (e.g., thecompounds can be sodium carbonate and sodium bicarbonate). The formedCO2 gas can form pores in the hardened material, such as pores having asize of about 1 micron to about 1000 microns, or about 10 microns toabout 100 microns. The porosity of a cured product of the curablecomposition not including any effervescent compound can be about 0. Theporosity of a cured product of the curable composition that includes aneffervescent compound can be about 5% to about 60%, or 5% or less, orless than, equal to, or more than about 10%, 15, 20, 25, 30, 35, 40, 45,50, 55%, or about 60% or more. In some embodiments, the effervescentagent produces a substantially continuous matrix of interconnected poresin the cured product of the curable calcium phosphate composition.

In some embodiments, the curable calcium phosphate composition includesdemineralized bone. The curable calcium phosphate composition caninclude any suitable proportion of demineralized bone, such as about0.001 wt % to about 40 wt % of the composition, or about 0.001 wt % orless, or less than, equal to, or more than about 0.01 wt %, 0.1, 1, 2,3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34,36, 38 wt %, or about 40 wt % or more. The demineralized bone caninclude or can be demineralized bone fibers.

In various embodiments, the present invention provides a use of thecurable calcium phosphate composition or a cured product thereof fortreatment of a joint disorder or condition. For example, the presentinvention can provide a method including using the calcium phosphatecomposition or cured product thereof as an orthopedic implant, such asusing the calcium phosphate composition in combination with a porousstructure as an orthopedic implant. The method can include implanting acured product of the curable calcium phosphate composition alone or witha porous structure, or can include implanting the curable calciumphosphate composition (e.g., alone or with a porous structure) andallowing the curable composition to cure.

Apparatus Including a Porous Structure

In various embodiments, the present invention provides an apparatusincluding a. porous structure at least partially in contact with thecurable calcium phosphate composition or a cured product thereof. Anysuitable proportion of the porous structure can be contacted with thecurable calcium phosphate composition. For example, about 0.001% toabout 100% of the outer surface of the porous structure can be incontact with the curable calcium phosphate composition or a curedproduct thereof, or about 0.001% or less, or less than, equal to, ormore than about 0.01%, 0.1, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16,18, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 82, 84, 86, 88,90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 99.9, 99.99, or about 99.999% ormore. In some embodiments, the inner volume (e.g., pore space) of theporous structure can include the curable calcium phosphate compositionor a cured product thereof, wherein 0% or about 0.001% to about 100% ofthe outer surface of the porous structure is in contact with the curablecalcium phosphate composition or a cured product thereof. Any suitableamount of the pore space of the porous structure can be filled with thecurable calcium phosphate composition or a cured product thereof, suchas 0%, or such as about 0.001% or less, or less than, equal to, or morethan about 0.01%, 0.1, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18,20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 82, 84, 86, 88, 90,91, 92, 93, 94, 95, 96, 97, 98, 99, 99.9, 99.99, or about 99.999%. Thecurable calcium phosphate composition or cured product thereof canextend into the pore space of the porous structure to any suitable depthfrom the surface, such as equal to, less than, or more than about 1 mm,2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32,34, 36, 38, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or about 100mm or more. In some embodiments, the curable calcium phosphatecomposition can extend throughout the pore space of the porousstructure.

The porous structure can include any suitable material. In variousembodiments, the porous structure includes a linear olefin polymer orcopolymer, an acrylonitrile butadiene styrene (ABS) polymer, an acrylicpolymer, a celluloid polymer, a cellulose acetate polymer, a cyclicolegin copolymer (COC), an ethylene-vinyl acetate (EVA) polymer, anethylene vinyl alcohol (EVOH) polymer, an ethylene n-butyl acetatepolymer (EnBA), a fluoroplastic, an ionomer, an acrylic/PVC alloy, aliquid crystal polymer (LCP), a polyacetal polymer (POM or acetal), apolyacrylate polymer, a polymethylmethacrylate polymer (PMMA), apolyacrylonitrile polymer (PAN or acrylonitrile), a polyamide polymer(PA or nylon), a polyamide-imide polymer (PAI), a polyaryletherketonepolymer (PAEK), a polybutadiene polymer (PBD), a polybutylene polymer(PB), a polybutylene terephthalate polymer (PBT), a polycaprolactonepolymer (PCL), a polychlorotrifluoroethylene polymer (PCTFE), apolytetrafluoroethylene polymer (PTFE), a polyethylene terephthalatepolymer (PET), a polycyclohexylene dimethylene terephthalate polymer(PCT), a polycarbonate polymer (PC), a polyhydroxyalkanoate polymer(PHA), a polyketone polymer (PK), a polyester polymer, a polyethylenepolymer (PE), a polyetheretherketone polymer (PEEK), apolyetherketoneketone polymer (PEKK), a polyetherketone polymer (PEK), apolyetherimide polymer (PEI), a polyethersulfone polymer (PIES), apolyethylenechlorinate polymer (PEC), a polyimide polymer (PI), apolylactic acid polymer (PLA), a polymethylpentene polymer (MP), apolyphenylene oxide polymer (PPO), a polyphenylene sulfide polymer(PPS), a polyphthalamide polymer (PPA), a polypropylene polymer, apolystyrene polymer (PS), a polysulfone polymer (PSL), apolytrimethylene terephthalate polymer (PTT), a polyurethane polymer(PU), a polyvinyl acetate polymer (PVA), a polyvinyl chloride polymer(PVC), a polyvinylidene chloride polymer (PVDC), a polyamideimidepolymer (PAI), a polyarylate polymer, a polyoxymethylene polymer (POM),a styrene-acrylonitrile polymer (SAN), or a combination thereof. Thelinear olefin polymer or copolymer can be ultra high molecular weightpolyethylene (UHMWPE), high-density polyethylene (HDPE), cross-linkedpolyethylene (PEX or XLPE), medium density polyethylene (MDPE), linearlow-density polyethylene (LLDPE), low-density polyethylene (LDPE), verylow-density polyethylene (VLDPE), a copolymer thereof, or a combinationthereof. The linear olefin polymer or copolymer can be a polymer orcopolymer of at least one of propene, butene, pentene, heptene, hexene,octene, nonene, decene, ethylene, a (C₁-C₁₀)alkylenoic acid, a vinyl(C₁-C₁₀)alkanoate ester, and a (C₁-C₁₀)alkyl(C₁-C₁₀)alkylenoate ester.Any one of more materials in this paragraph can independently form anysuitable proportion of the porous structure, such as 0%, such as about0.001 wt % to about 99 wt %, or about 0.001 wt % to about 50 wt %, orabout 0.001 wt % or less, or equal to or less than about 0.01 wt %, 0.1,1, 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, 18, 20, 25, 30, 35, 40, 45, 50, 55,60, 65, 70, 75, 80, 85, 90, 95, 96, 97, 98, 99, 99.9, 99.99 wt %, orabout 99.999 wt % or more.

The one or more materials in the porous structure can include aplurality of ligaments. The plurality of ligaments can define the poresof the porous structure. The open spaces between the ligaments form amatrix of continuous channels having few or no dead ends, such thatgrowth of soft tissue and/or bone through the porous structure issubstantially uninhibited. The porous structure can be suited forcontacting bone, soft tissue, or a combination thereof, and in thisregard, can be useful as bone substitutes and other implants and implantcomponents that are receptive to cell and tissue ingrowth, for example,by allowing bony tissue or other tissue to grow into the porousstructure over time to enhance fixation (e.g., osseointegration) betweenthe structure and surrounding bodily structures.

The porous structure can include or can be a prosthetic implant, such asan orthopedic implant, such as an orthopedic implant for implantation ina hip, knee, ankle, shoulder, spine, jaw, or elbow. The porous structurecan include or can be a prosthetic acetabular component, a prostheticproximal femoral component, a prosthetic distal femoral component, aprosthetic tibial component, a prosthetic humeral component, aprosthetic dental component, a prosthetic spinal component, or acombination thereof The porous structure can include or can be anacetabular cup, a tibial cone, a glenoid implant, or a distaltibia-tallus fusion body.

In various embodiments, the present invention provides a use of theapparatus for treatment of a joint disorder or condition. For example,the present invention can provide a method including using the apparatusas an orthopedic implant. The method can include implanting theapparatus (e.g., forming the apparatus outside the body and thenimplanting the apparatus) or forming the apparatus in vivo (e.g.,implanting the porous structure, adding the curable calcium phosphatecomposition or cured product thereof, and allowing the curable calciumphosphate composition to cure).

Porous Metal Structure

The porous structure can include or can be a porous metal structure. Theporous metal structure can be any suitable proportion of the porousstructure, such as about 0.001 wt % to about 100 wt %, or about 50 wt %to about 100 wt %, or about 0.001 wt % or less, or less than, equal to,or greater than about 0.01 wt %, 0.1, 1, 2, 3, 4, 5, 6, 8, 10, 12, 14,16, 18, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 82, 84, 86,88, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 99.9, 99.99, or about 99.999wt % or more. In some embodiments, the porous structure includes aporous metal structure that is at least partially coated with or isfully encompassed by a porous non-metallic structure, wherein the porousnon-metallic structure includes any one or more non-metallic materialsdescribed herein as suitable materials for the porous structure, such asPEEK Any suitable amount of the surface area of a porous metal structurecan be coated with a porous non-metallic structure in the porousstructure, such as about 0.01% to about 100%, or about 80% to about100%, or about 0.01% or less, or less than, equal to, or greater thanabout 0.1, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, 20, 25, 30,35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 82, 84, 86, 88, 90, 91, 92, 93,94, 95, 96, 97, 98, 99, 99.9, or about 99.99% or more.

The porous metal structure can include any suitable metal. The metal canbe a biocompatible metal. The metal can be tantalum, titanium, niobium,hafnium, tungsten, an alloy thereof (e.g., a tantalum alloy, a titaniumalloy, a niobium alloy, a hafnium alloy, a tungsten alloy, a tantalumniobium alloy), or a combination thereof. The porous metal structure caninclude tantalum metal.

The porous metal structure can include a porous substrate including aplurality of ligaments. The plurality of ligaments can define the poresof the porous substrate and of the porous metal structure. The porousmetal structure can include a biocompatible metal coating on (e.g.,applied to) the plurality of ligaments of the porous substrate.

The porous substrate can have a lower density than the biocompatiblemetal thereon. The porous substrate can include or can be a foam havinga lower density than the biocompatible metal thereon. The poroussubstrate can include or can be reticulated vitreous carbon foam. Forexample, the reticulated vitreous carbon (RVC) foam can have a pluralityof vitreous carbon ligaments that define dodecahedron (12-sided) porestherebetween. RVC foam is commercially available in porosities rangingfrom 10 to 200 pores per cubic inch (i.e., about 0.61 to about 12 poresper cubic cm), and more specifically in porosities of 65, 80, and 100pores per cubic inch (i.e., about 3.97, 4.88, or about 6.10 pores percubic cm, respectively). Such RVC foam substrates may be formed bypyrolyzing an open-cell, polymer foam.

The biocompatible metal on the porous substrate can be any suitablebiocompatible metal. The biocompatible metal can include a Group IV-VIrefractory metal. The biocompatible metal can be tantalum, titanium,niobium, hafnium, tungsten, an alloy thereof (e.g., a tantalum alloy, atitanium alloy, a niobium alloy, a hafnium alloy, a tungsten alloy, atantalum niobium alloy), or a combination thereof. The biocompatiblemetal can be tantalum. The biocompatible metal can be deposited on theporous substrate, such as via chemical vapor deposition. Thebiocompatible metal can cover any suitable amount of the surface area ofthe porous substrate (e.g., including the outer surface and the innersurfaces that form the pores), such as about 10% to about 100%, or about90% to about 100%, or about 10% or less, or less than, equal to, or morethan about 15%, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 72, 74, 76,78, 80, 82, 84, 86, 88, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 99.9,99.99, or about 99.999% or more.

The porous metal structure can be suited for contacting bone, softtissue, or a combination thereof, and in this regard, can be useful asbone substitutes and other implants and implant components that arereceptive to cell and tissue ingrowth, for example, by allowing bonytissue or other tissue to grow into the porous structure over time toenhance fixation (e.g., osseointegration) between the structure andsurrounding bodily structures. Such structures can provide lightweight,yet strong porous implants. Certain porous metal structures, despitehaving such high porosities, are capable of withstanding extrememechanical loads at the time of implantation and over long periods oftime (for example, where a highly porous, three-dimensional metallicstructure is forcefully impacted and press fit into a bone, by itself orconnected to another implant, and maintains its shape during impactionand following many months or years of service in the body). Suchstructures can be manufactured according to any suitable technique orprocess. An example of a porous metal structure is produced usingTrabecular Metal™ Technology available from Zimmer, Inc., of Warsaw,Ind. Trabecular Metal™ is a trademark of Zimmer, Inc. Such a materialmay be formed from a reticulated vitreous carbon foam substrate which isinfiltrated and coated with a biocompatible metal, such as tantalum, bya chemical vapor deposition (“CVD”) process in the manner disclosed indetail in U.S. Pat. No. 5,282,861 and in Levine, B. R., et al.,“Experimental and Clinical Performance of Porous Tantalum in OrthopedicSurgery,” Biomaterials 27 (2006) 4671-4681, the disclosures of which areexpressly incorporated herein by reference.

In some instances, the porous metal structure can be a highly porous,three-dimensional metallic structure that is fabricated using aselective laser sintering (SLS) or other additive manufacturing-typeprocess such as direct metal laser sintering or electron beam melting.In one example, a three-dimensional (3-D) porous article is produced inlayer-wise fashion from a laser-fusible powder (e.g., a single-componentmetal powder), which is deposited one layer at a time. The powder isfused, remelted or sintered, by the application of laser energy that isdirected to portions of the powder layer corresponding to a crosssection of the article. After the fusing of the powder in each layer, anadditional layer of powder is deposited, and a further fusing step iscarried out, with fused portions or lateral layers fusing so as to fuseportions of previous laid layers until a three-dimensional article iscomplete. In certain embodiments, a laser selectively fuses powderedmaterial by scanning cross-sections generated from a 3-D digitaldescription of the article (e.g., from a CAD file or scan data) on thesurface of a powder bed. Complex geometries can be created using suchtechniques, and in some instances, net shape and near net shape implantsare constructed. In some embodiments, a non-porous or essentiallynon-porous base substrate will provide a foundation upon which athree-dimensional porous structure will be built and fused thereto usinga SLS or other additive manufacturing-type process. Such substrates canincorporate one or more of a variety of biocompatible metals such as anyof those disclosed herein.

Generally, the porous metal structure includes a large plurality ofligaments that define open voids (e.g., pores) or channels between theligaments. The open spaces between the ligaments form a matrix ofcontinuous channels having few or no dead ends, such that growth of softtissue and/or bone through the open porous metal is substantiallyuninhibited. According to sonic aspects of the present disclosure,exterior surfaces of an open porous metal structure can featureterminating ends of the above-described ligaments. Such terminating endscan be referred to as struts, and they can generate a high coefficientof friction along an exposed porous metal surface. Such features canimpart an enhanced affixation ability to an exposed porous metal surfacefor adhering to bone and soft tissue. Also, when such highly porousmetal structures are coupled to an underlying substrate, a smallpercentage of the substrate may be in direct contact with the ligamentsof the highly porous structure; for example, approximately 15%, 20%, or25%, of the surface area of the substrate may be in direct contact withthe ligaments of the highly porous structure.

The porous metal structure can be fabricated such that it includes avariety of densities in order to selectively tailor the structure forparticular orthopedic applications (for example, by matching thestructure to surrounding natural tissue in order to provide an improved.matrix for tissue ingrowth and mineralization). Such structures can beisotropic or anisotropic. In this regard, according to certainembodiments, an open porous metal structure may be fabricated to have asubstantially uniform porosity, density, void (pore) size, pore shape,and/or pore orientation throughout, or to have one or more features suchas porosity, density, void (pore) size, pore shape, and/or poreorientation being varied within the structure, or within a portionthereof. For example, a porous metal structure may have a different poresize, pore shape, and/or porosity at different regions, layers, andsurfaces of the structure. The ability to selectively tailor thestructural properties of the open porous metal enables, for example,tailoring of the structure for distributing stress loads throughout thesurrounding tissue and. promoting tissue growth into and within the openporous metal. In some instances, a highly porous, three-dimensionalmetallic structure, once formed, will be infiltrated and coated with oneor more coating materials such as biocompatible metals such as any ofthose disclosed herein.

The porous metal structure can have any suitable relative density,wherein the relative density of the porous metal structure is apercentage obtained by dividing an actual density of the porous metalstructure (e.g., of the porous metal structure alone, without thecurable calcium phosphate composition or cured product thereof therein)by a theoretical density of the biocompatible metal of the coating. Therelative density can be about 12% to about 50%, or about 12% or less, orless than, equal to, or more than about 13%, 14, 15, 16, 17, 18, 19, 20,22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 41, 42, 43, 44, 45, 46, 47, 48,49, or about 50% or more.

The porous metal structure can have any suitable specific compressivestrength. For example, the porous metal structure (e.g., the porousmetal structure alone, without the curable calcium phosphate compositionor cured product thereof therein) can have a specific compressivestrength of about 50 MPa to about 2,000 MPa, or about 200,000 psi, orabout 100 MPa to about 500 MPa, or about 50 MPa or less, or less than,equal to, or more than about 60 MPa, 70, 80, 90, 100, 110, 120, 130,140, 150, 160, 165 (i.e., about 24,000 psi), 170, 175, 180, 185, 190,195, 200, 225, 250, 275, 300, 350, 400, 450, 500, 600, 700, 800, 900,1,000, 1,250, 1,500, 1,750, 2,000, 5,000, 10,000, 20,000, 50,000,100,000, 150,000, or about 200,000 psi or more.

Method of Forming The Apparatus

Various embodiments of the present invention provide a method of formingthe apparatus including the porous structure at least partially incontact with the curable calcium phosphate composition or a curedproduct thereof. The method can be any suitable method that generates anembodiment of the apparatus described herein. The method can includeplacing the curable calcium phosphate composition at least partially incontact with the porous structure to form the apparatus. The placing caninclude placing the curable calcium phosphate composition into theporous structure (e.g., into at least some of the pore space in theporous structure), around the porous structure (e.g., in contact with anexternal surface of the porous structure), or a combination thereof. Theplacing can be any suitable placing, such as injecting (e.g., from asyringe via a needle), perfusing, placing by hand or with a spatula orother surgical tool, diffusing, and the like. The method can includeallowing the curable calcium phosphate composition to cure.

The method can be performed in vivo, such as including some steps invivo (with other steps outside the body) or all steps performed in vivo.The method can include or can be a primary or revision surgery, such asof a hip implant, a leg implant, a shoulder implant, a. jaw implant, aspine implant, or an ankle implant. The method can include treatment ofosteolytic lesions (e.g., by implanting the curable composition, curedproduct thereof, porous structure, or any combination thereof, incontact therewith). The method can be a surgical method, such as whereinthe curable calcium phosphate composition is placed in contact with theporous structure in vivo, or wherein the curable calcium phosphatecomposition is placed in contact with the porous structure outside thebody and the apparatus is then implanted. The curable calcium phosphatecomposition can be allowed to cure before implantation or afterwards.

In various embodiments, the method can include a primary implantationsurgery or revision surgery for an acetabular cup implant, asillustrated in FIG. 1. The acetabular cup 100 can include a porousstructure with a porosity similar to trabecular bone on the side thatcontacts the pelvis 105, and a smooth surface on the side that contactsthe proximal femur 120 (not shown). The acetabular cup 100 can be usedwith cannulated fenestrated screws 115 to anchor the cup to the pelvis105. The curable calcium phosphate composition 110 is placed in regionsthat facilitate augmentation of screw fixation. The curable calciumphosphate composition 110 is placed in regions that augment fixation ofthe acetabular cup 100 to the acetabulum of the pelvis 105. At leastsome of the curable calcium phosphate composition 110 penetrates thepores of the porous structure of the acetabular cup 100. The curablecalcium phosphate composition 110 can reduce or eliminate loosening ofthe implanted cup due to poor quality of bone in the acetabulum. Thecurable calcium phosphate composition 110 can create a continuousosteoconductive region between the porous structure and the acetabulum.

In various embodiments, the method can include a primary implantationsurgery or revision surgery for a tibial cone implant, as illustrated inFIGS. 2A-B. FIG. 2A shows an end-on cutaway view of a proximal tibia 200having a tibial cone implant 205 therein, wherein the tibial coneimplant 205 is a porous structure. FIG. 2B shows a side cutaway view ofthe tibia 200 having the tibial cone implant 205 therein. The implantincludes the curable calcium phosphate composition 210 between theporous structure 205 and the bone of the tibia 200. The tibial coneimplant 205 has a porosity similar to trabecular bone. The curablecalcium phosphate material at least partially penetrates the porousstructure of the tibial cone implant 205. The curable calcium phosphatematerial 210 is placed in regions of the tibia to augment the fixationof the cone implant 205 and eliminate mismatch between the endostealcontour of the tibial metaphysis that accepts the tibial cone implant205. The curable calcium phosphate material 210 reduces or eliminatesloosening of the implanted tibial cone implant 205 due to poor qualityof bone in the proximal tibia 200. The curable calcium phosphatematerial 210 creates a continuous osteoconductive region between thetibial cone implant 205 and the tibia 200.

In various embodiments, the method can include a primary implantationsurgery or revision surgery for a glenoid implant, as illustrated inFIG. 3. The scapula 300 includes a glenoid pegged implant 305 whichincludes the porous structure 306 and a smooth articulating surface 307.The implant includes the curable calcium phosphate composition 310between the porous structure 306 and the bone 300. The porous structure306 has a porosity similar to trabecular bone. The curable calciumphosphate composition 310 provides structural fixation of the peggedcomponents of the implant 305 within the scapula 300 to augment fixationtherein. The curable calcium phosphate composition 310 at leastpartially penetrates into the pores of the porous structure 306. Thecurable calcium phosphate composition 310 improves the seating of theimplant 305 by filling out small spaces between the bone 300 and theimplant 305, such as may result from irregularities after reaming. Thefixation of pegged glenoid implant 305 has better chances of integratingif the holes are filled with an osteoconductive material. The curablecalcium phosphate material 310 is a flowable material that can bedelivered with a syringe or can be a moldable material which can beinserted with pure finger pressure. The curable calcium phosphatematerial 310 can reduce or eliminate loosening of the implant 305 due topoor quality of bone in the scapula 300 or due to gaps between thescapula 300 and the implant 305. The curable calcium phosphate material310 can create a continuous osteoconductive region between the implant305 and the bone 300.

In various embodiments, the method can include a primary implantationsurgery or revision surgery for a total ankle replacement spacer, asillustrated in FIG. 4. The distal tibia 400 and the talus 405 includetibiotalar porous fusion implant 410, which is a porous structure havingporosity similar to trabecular bone. A curable calcium phosphatecomposition 415 is inside the implant 410 and is between the ends of theimplant 410 and the distal tibia 400 and the talus 405. The curablecalcium phosphate composition 415 can be placed in the implant 410 priorto implantation or the implant 410 can be filled with the composition415 after implantation using a port or delivery hole in the implant 410(not shown). The curable calcium phosphate composition 415 augments thefixation of the implant 410, and eliminates mismatch between the contourof the distal tibia 400 and the implant 410, such as resulting fromirregularities after reaming distal tibia 400. The curable calciumphosphate composition 415 reduces or eliminates loosening of the implant410 due to poor quality of bone in the fusion mass. The curable calciumphosphate composition 415 creates a continuous osteoconductive regionbetween the implant 410 and the tibia 400 and talus 405. The curablecalcium phosphate composition 415 can be inductive or conductive tofacilitate formation of a fusion mass (not shown).

EXAMPLES

Various embodiments of the present invention can be better understood byreference to the following Examples which are offered by way ofillustration. The present invention is not limited to the Examples givenherein.

Part I Example 1-1

A low density lyophilized calcium carboxymethylcellulose is mixed in thedry state with a reactive calcium deficient (Ca:P ratio of less than1.67) calcium phosphate (an amorphized 1:1 mixture by mass of amorphouscalcium phosphate and dicalcium phosphate dihydrate), forming a mixturethat is about 5.5 wt % calcium carboxymethylcellulose and about 94.5 wt% amorphous calcium phosphate. The dry powder mixture is then mixed withdeionized water, forming a mixture that is 45 wt % deionized water. Aflowable paste results which, upon dissociation of Ca²⁺ ions, hardensinto a crystalline solid. The flowable paste perfuses porous trabecularstructures without phase separation of the calcium phosphate from theaqueous cellulose derivative.

Example 1-2

Sodium alginate is mixed in solution with a 1:1 by weight mixture ofreactive amorphous calcium phosphate and a calcium deficient carbonateapatite (having a Ca:P molar ratio of less than 1.67 with CO₃ ²⁻ ionsoccupying both A (OH⁻ substitutions) and B (PO₄ ³⁻ substitutions) sitesin the apatite lattice), forming a mixture that has a weight ratio ofsodium alginate to the mixture of reactive amorphous calcium phosphateand the calcium deficient carbonate apatite of 5.5:94.5. The mixture islyophilized. The dry powder is then mixed with deionized water to form amixture that is 45 wt % deionized water. A flowable paste results which,upon dissociation of Ca²⁺ ions from the carbonate apatite, hardens intoa crystalline solid. The flowable paste perfuses porous trabecularstructures without phase separation of the calcium phosphate from theaqueous sodium alginate.

Example 1-3

Sodium carboxymethylcellulose is lyophilized with CaCO₃ and mixed in thedry state with a reactive calcium deficient amorphous calcium phosphate(an amorphized 1:1 mixture by mass of amorphous calcium phosphate anddicalcium phosphate dihydrate) with a sodium carboxymethylcellulose toreactive calcium deficient amorphous calcium phosphate weight ratio of5.5:94.5. The dry powder is then mixed with autologous blood to form amixture that is 45 wt % autologous blood. A flowable paste resultswhich, upon dissociation of Ca²⁺ and metal carbonate ions, hardens intoa crystalline carbonate apatite solid. The flowable paste perfusesporous trabecular structures without phase separation of the calciumphosphate from the aqueous cellulose derivative.

Part II

This Part compares the injectability and performance of various calciumphosphate bone substitute materials (BSMs) that were injected into aporous metal Trabecular Metal™ (TMT) block (1.614 in×1.732 in).Performance characteristics included measurement of forces required toextrude the BSM into the TMT block in addition to qualitative assessmentand gross histology. Mixing of BSMs was performed in PMDS (precisionmixing and delivery system, P/N: 31-0001). For the purpose of thistesting all materials were gamma irradiated at (25-35) KGy.

Materials. The following materials were used in this Part: Physiologicalsaline (0.9% NaCl, VWR®); 1 cc Medallion® syringes (P/N: 30-1098);Texture Technologies TA-HD plus (Stable Micro Systems); TMT blocks(1.614 in×1.732 in); 24×1.4 cc PMDS (P/N: 31-0001); 4 funnels for MedMixAG (PSN: 30-1124); 6 Internal pin (P/N: 30-1125); 6>7.5 g Sample #2powder in MedMix AG syringes (PMDS); and 6×5 cc Sample #1 powder inMedMix AG syringes (PMDS). Sample #1 was 100% CaP₃. Sample #2 was 91.5%CaP₃, 5 wt % EfferSoda® (a mixture of 10 wt % sodium carbonate and 90 wt% sodium bicarbonate), and 3.5 wt % carboxymethylcellulose. The CaP₃ wasa 1:1 (by weight) mixture of ball-milled amorphous calcium phosphate anddicalcium phosphate dehydrate. The ball-milling was performed using a 10mm diameter high-density ZrO₂ ball for 3 hours. The amorphous calciumphosphate was prepared using a low temperature double decompositiontechnique, by adding rapidly a calcium solution (0.36 M), to phosphatesolution (0.16 M) in a basic (pH˜13) media. The amorphous phase was thenstabilized using three crystal growth inhibitor ions (CO₃ ²⁻, Mg²⁺, andP₂O₇ ⁴⁻), freeze-dried, and heated (450° C., 1 h) to remove additionalmoisture and some crystal growth inhibitors. The dicalcium phosphatedehydrate also prepared using wet chemistry by adding rapidly a calciumsolution (0.30 M), to phosphate solution (0.15 M) in a slightly acidic(pH˜5-6) media. During precipitation, the chemical composition of thedicalcium phosphate dehydrate was controlled to approximately 10 to 25%(w/w) apatite. The dicalcium phosphate dehydrate wet cake was thenvacuum dried (6 hat 37° C.), and milled to achieve a particle size ofless than 125 μm.

Testing facilities. The testing facilities and the services provided byeach test facility are described in Table 1.

TABLE 1 Test facilities. Test Test facility Address method Isomedix 435Whitney Street Gamma Irradiation Northborough, MA 01532 at 25-35 kGyPhone#(508)393-9323 Zimmer 38 Sidney St. Extrusion Biomet EtexCambridge, MA 02139 (Injectability) Zimmer Parsippany, NJ Sectioning andBiomet TMT gross histology

TMT blocks. FIGS. 5A-D illustrates the dimensions of the TMT block,which had a void in the middle. FIG. 5A illustrates a top view of theTMT block. FIG. 5B illustrates a cut-away view of the TMT block takenalong line A-A from FIG. 5A. FIG. 5C illustrates a side view of the TMTblock. FIG. 5D illustrates a cut-away view of the TMT block taken alongline B-B from FIG. 5D.

Example 2-1. Testing of Samples

All testing was conducted using sterile Samples. Each ETEX product wastested according to the schedule outlined in Table 2.

TABLE 2 Testing schedule. Type of Test Number of Cannula Method BlocksMaterial 11G Cannula Extrusion Force 3 Sample #1 (Maximum and Average)11G Cannula Extrusion Force 4 Sample #2 (Maximum and Average)

Samples were hydrated with 0.9% sodium chloride USP saline according tothe appropriate L/P ratio per each product (Sample 1=0.5 mL/g, Sample2=0.4 mL/g) and mixed in MedMix AG syringes for approximately 60 secondsto achieve a paste with a smooth consistency. The BSM Samples weretested to measure injection force through an 8 G cannula for EquivaBoneand through an 11 G cannula for all other products. The 1 cc Medallion®syringes (PIN: 30-1098) were attached with the 8 G and 11G cannulas intothe hole (0.020 in) of the TMT blocks. Each Sample paste was extrudedinto a TMT block from a 1 cc syringe, and the maximum filling forcerequired to make the extrusion was measured. The extrusion testingset-up is illustrated in FIG. 6.

Example 2-2. Results

The raw data is given in Table 3. A summary of the results is given inTable 4.

Injection of Sample #1 into the TMT block showed forces higher than theaccepted standard of 10 kgf. This was due to a complete fill of thesimulated void and inability of the material to intrude the porousstructure any further. On the contrary, the Sample #2 materialconsistently showed injection forces significantly lower than theaccepted standard, even after the void was filled. One block was testedwith 10 cc of Sample #2 and it continued to show lower injection forcesin spite of the excess material injected into the block.

TABLE 3 Raw data. Mean Maximum 1 cc TMT L/P force injection force SampleSize syringe # block # (mL/g) (kg) (kg) Comments 1-1 5 cc 1 1 0.5 0.0710.30 Injected through 11 G cannula 2 0.21 0.72 3 0.31 1.60 4 0.554 2.715 3.388 9.83 Hard to plunge paste by hand due to phase 1-2 5 cc 1 2 0.50.047 0.10 Injected through 11 G cannula 2 0.221 1.10 3 0.296 1.03 43.517 22.62 5 n/a n/a Hard to plunge paste by hand due to phase 1-3 5 cc1 3 0.5 0.053 0.42 Injected through 11 G cannula 2 0.072 0.42 3 0.1980.71 4 0.366 1.06 5 3.309 12.67 Easy to plunge 2-1 5 cc 1 4 0.5 1.622.57 Injected through 11 G cannula 2 2.945 3.76 3 2.529 3.36 4 3.1324.01 5 2.733 3.61 Easy to plunge 2-2 5 cc 1 5 0.4 1.721 2.92 Injectedthrough 11 G cannula 2 2.695 3.47 3 2.774 3.76 4 2.702 3.78 5 2.688 3.76 0.706 3.1 Only plunged by instrument (Texture) 2-3 5 cc 1 6 0.4 1.733.05 Injected through 11 G cannula 2 1.852 2.54 3 2.473 3.30 4 2.9033.95 5 3.221 4.24 6 0.681 5.69 Only plunged by instrument (Texture) 2-410 cc  1 7 0.4 2.481 4.195 Injected through 11 G cannula. On 2 3.3424.504 syringe #9, paste was injected but 3 3.406 4.560 after 9 cc thepaste came out from 4 3.479 4.635 the block. 5 4.034 5.357 6 4.409 5.8097 4.34 6.110 8 4.733 7.513 9 3.783 5.485 10 6.932 8.846 Only plunged byinstrument (Texture)

TABLE 4 Summary of results. Mean Maximum Force Force BSM Seq (kgf) (kgf)Comments Sample 1 0.06 ± 0.01 0.28 ± 0.16 #1 2 0.17 ± 0.08 0.74 ± 0.34 5cc 3 0.27 ± 0.06 1.11 ± 0.45 N = 3 4 1.48 ± 1.77  8.80 ± 12.00 Highmaximum force due to complete defect fill and limited intrusion. 5 3.35± 0.06 11.25 ± 2.01  High maximum force due to complete defect fill andlimited intrusion. Sample 1 1.67 ± 0.07 2.87 ± 0.27 #2 2 2.46 ± 0.643.43 ± 0.35 5 cc 3 2.39 ± 0.48 3.22 ± 0.62 N = 3 4 2.77 ± 0.33 3.70 ±0.37 5 2.77 ± 0.11 3.75 ± 0.17 Sample 1 2.48 4.20 #2 2 3.34 4.50 10 cc 33.45 4.56 N = 1 4 3.48 4.64 5 4.03 5.36 6 4.41 5.81 7 4.34 6.11 8 4.737.51 9 3.78 5.49 10 6.93 8.85

FIGS. 7A-B illustrate photographs of Sample #2 after infusion thereofthrough into the TMT block. The TMT block was cut in order to bettershow the Sample in the block. The block sections showed penetration ofSample #2 through porous TMT block. The material showed intrusion andinter-digitation with the metal surrounding the void at the center ofthe TMT block.

Example 2-3. Analysis

Sample #2 showed qualitative intrusion into the porous TMT block. Theinjection forces for Sample #2 were also below the accepted standard of10 kgf, the approximate capability of an average human hand. Incomparison, injection forces for Sample #1 were higher due to limitedintrusion.

The terms and expressions that have been employed are used as terms ofdescription and not of limitation, and there is no intention in the useof such terms and expressions of excluding any equivalents of thefeatures shown and described or portions thereof, but it is recognizedthat various modifications are possible within the scope of theembodiments of the present invention. Thus, it should be understood thatalthough the present invention has been specifically disclosed byspecific embodiments and optional features, modification and variationof the concepts herein disclosed may be resorted to by those of ordinaryskill in the art, and that such modifications and variations areconsidered to be within the scope of embodiments of the presentinvention.

Additional Embodiments

The following exemplary embodiments are provided, the numbering of whichis not to be construed as designating levels of importance:

Embodiment 1 provides a curable calcium phosphate compositioncomprising:

calcium phosphate; and

a perfusion modifier.

Embodiment 2 provides the curable calcium phosphate composition ofEmbodiment 1, further comprising a physiologically acceptable fluid.

Embodiment 3 provides the curable calcium phosphate composition ofEmbodiment 2, wherein the physiologically acceptable fluid is about0.001 wt % to about 99.999 wt % of the composition.

Embodiment 4 provides the curable calcium phosphate composition of anyone of Embodiments 2-3, wherein the physiologically acceptable fluidcomprises water, saline, phosphate buffer, biological fluid, or acombination thereof.

Embodiment 5 provides the curable calcium phosphate composition ofEmbodiment 4, wherein the biological fluid comprises blood, a bloodcomponent, a blood product, milk, urine, saliva, seminal fluid, vaginalfluid, synovial fluid, lymph fluid, amniotic fluid, the fluid within ayolk sac of an egg, chorion of an egg, allantois of an egg, sweat,tears, or a combination thereof.

Embodiment 6 provides the curable calcium phosphate composition of anyone of Embodiments 1-5, wherein the calcium phosphate is about 0.001 wt% to about 99.999 wt % of the composition.

Embodiment 7 provides the curable calcium phosphate composition of anyone of Embodiments 1-6, wherein the calcium phosphate is about 40 wt %to about 70 wt % of the composition.

Embodiment 8 provides the curable calcium phosphate composition of anyone of Embodiments 1-7, wherein the calcium phosphate comprisesamorphous calcium phosphate, poorly crystalline calcium phosphate,hydroxyapatite, carbonated apatite, monocalcium phosphate, calciummetaphosphate, heptacalcium phosphate, dicalcium phosphate dihydrate,tetracalcium phosphate, octacalcium phosphate, calcium pyrophosphate,tricalcium phosphate, or a combination thereof.

Embodiment 9 provides the curable calcium phosphate composition of anyone of Embodiments 1-8, wherein the calcium phosphate comprisesamorphous calcium phosphate and a second calcium phosphate comprisingpoorly crystalline calcium phosphate, hydroxyapatite, carbonatedapatite, monocalcium phosphate, calcium metaphosphate, heptacalciumphosphate, dicalcium phosphate di hydrate, tetracalcium phosphate,octacalcium phosphate, calcium pyrophosphate, tricalcium phosphate, or acombination thereof.

Embodiment 10 provides the curable calcium phosphate composition of anyone of Embodiments 1-9, wherein the calcium phosphate comprisesamorphous calcium phosphate and dicalcium phosphate dihydrate.

Embodiment 11 provides the curable calcium phosphate composition of anyone of Embodiments 1-10, wherein the perfusion modifier is about 0.001wt % to about 50 wt % of the composition.

Embodiment 12 provides the curable calcium phosphate composition of anyone of Embodiments 1-11, wherein the perfusion modifier is about 0.5 wt% to about 10 wt % of the composition.

Embodiment 13 provides the curable calcium phosphate composition of anyone of Embodiments 1-12, wherein the perfusion modifier is a polymer.

Embodiment 14 provides the curable calcium phosphate composition of anyone of Embodiments 1-13, wherein the perfusion modifier is apolysaccharide, a nucleic acid, a carbohydrate, a protein, apolypeptide, a poly(α-hydroxy acid), a poly(lactone), a poly(aminoacid), a poly(anhydride), a poly(orthoester), apoly(anhydride-co-imide), a poly(orthocarbonate), a poly(α-hydroxyalkanoate), a poly(dioxanone), a poly(phosphoester), sodium alginate,alginic acid, arabic gum, guar gum, xantham gum, gelatin, chitin,chitosan, chitosan acetate, chitosan lactate, chondroitin sulfate,N,O-carboxymethyl chitosan, a dextran, fibrin glue, glycerol, hyaluronicacid, sodium hyaluronate, a cellulose, a glucosamine, a proteoglycan, astarch, lactic acid, a poly(ethylene oxide-co-propylene oxide), sodiumglycerophosphate, collagen, glycogen, a keratin, silk, poly(L-lactide)(PLLA), poly(D,L-lactide) (PDLLA), polyglycolide (PGA),poly(lactide-co-glycolide) (PLGA), poly(L-lactide-co-D, L-lactide),poly(D,L-lactide-co-trimethylene carbonate), polyhydroxybutyrate (PHB),poly(ϵ-caprolactone), poly(ϵ-valerolactone), poly(γ-butyrolactone),poly(caprolactone), polyacrylic acid, polycarboxylic acid,poly(allylamine hydrochloride), poly(diallyldimethylammonium chloride),poly(ethyleneimine), polypropylene fumarate, polyvinyl alcohol,polyvinylpyrrolidone, polyethylene, polymethylmethacrylate, carbonfibers, poly(ethylene glycol), poly(ethylene oxide), poly(vinylalcohol), poly(vinylpyrrolidone), poly(ethyloxazoline), poly(ethyleneoxide)-co-polypropylene oxide) block copolymers, poly(ethyleneterephthalate)polyamide, copolymers thereof, or a combination thereof.

Embodiment 15 provides the curable calcium phosphate composition of anyone of Embodiments 1-14, wherein the perfusion modifier ismethylcellulose, carboxymethylcellulose, hydroxypropylmethylcellulose,hydroxyethylcellulose, a salt thereof, or a combination thereof.

Embodiment 16 provides the curable calcium phosphate composition of anyone of Embodiments 1-15, wherein the perfusion modifier is a lyophilizedperfusion modifier.

Embodiment 17 provides the curable calcium phosphate composition of anyone of Embodiments 1-16, further comprising a biologically activemodifier.

Embodiment 18 provides the curable calcium phosphate composition ofEmbodiment 17, wherein the biologically active modifier is about 0.001wt % to about 40 wt % of the composition.

Embodiment 19 provides the curable calcium phosphate composition of anyone of Embodiments 17-18, wherein the biologically active modifier isabout 0.001 wt % to about 10 wt % of the composition.

Embodiment 20 provides the curable calcium phosphate composition of anyone of Embodiments 17-19, wherein the biologically active modifier is atleast one of an antibody, an antibiotic, a polynucleotide, apolypeptide, a protein, an anti-cancer modifier, a growth factor, avaccine, or a combination thereof.

Embodiment 21 provides the curable calcium phosphate composition of anyone of Embodiments 1-20, further comprising a binder.

Embodiment 22 provides the curable calcium phosphate composition ofEmbodiment 21, wherein the binder is about 0.001 wt % to about 20 wt %of the composition.

Embodiment 23 provides the curable calcium phosphate composition of anyone of Embodiments 21-22, wherein the binder is about 0.001 wt % toabout 5 wt % of the composition.

Embodiment 24 provides the curable calcium phosphate composition of anyone of Embodiments 21-23, wherein the binder is at least one of a) apolysaccharide, a nucleic acid, a carbohydrate, a protein, apolypeptide, a poly(α-hydroxy acids), a poly(lactone), a poly(aminoacid), a poly(anhydride), a poly(orthoester), apoly(anhydride-co-imide), a poly(orthocarbonate), a poly(α-hydroxyalkanoate), a poly(dioxanone), a poly(phosphoester), poly(L-lactide)(PLLA), poly(D,L-lactide) (PDLLA), polyglycolide (PGA),poly(lactide-co-glycolide (PLGA), poly(L-lactide-co-D, L-lactide),poly(D,L-lactide-co-trimethylene carbonate), polyhydroxybutyrate (PHB),poly(ϵ-caprolactone), poly(ϵ-valerolactone), poly(γ-butyrolactone),poly(caprolactone), polyacrylic acid, polycarboxylic acid,poly(allylamine hydrochloride), poly(diallyldimethylammonium chloride),poly(ethyleneimine), polypropylene fumarate, polyvinyl alcohol,polyvinylpyrrolidone, a polyethylene, polymethylmethacrylate, a carbonfiber, poly(ethylene glycol), poly(ethylene oxide), poly(vinyl alcohol),poly(vinylpyrrolidone), poly(ethyloxazoline), a poly(ethyleneoxide)-co-polypropylene oxide) block copolymer, poly(ethyleneterephthalate)polyamide, and copolymers thereof; b) a homo- orco-polymer having one or more monomers selected from the groupconsisting of acrolein potassium, (meth)acrylamides, (meth)acrylic acidand salts thereof, (meth)acrylates, acrylonitrile, ethylene, ethyleneglycol, ethyleneimine, ethyleneoxide, styrene sulfonate, vinyl acetate,vinyl alcohol, vinyl chloride, and vinylpyrrolidone); c) a polyphenolcomplexing agent selected from a gallotannin, a ellagitannin, ataragallotannin, a caffetannin, a proanthocyanidin, catechin,epicatechin, chlorogenic acid, and arbutin; and d) an agent selectedfrom alginic acid, arabic gum, guar gum, xanthan gum, gelatin, chitin,chitosan, chitosan acetate, chitosan lactate, chondroitin sulfate,N,O-carboxymethyl chitosan, a dextran, fibrin glue, glycerol, hyaluronicacid, sodium hyaluronate, a cellulose, a glucosamine, a proteoglycan, astarch, lactic acid, a poly(ethylene oxide-co-propylene oxide), sodiumglycerophosphate, collagen, glycogen, a keratin, and silk.

Embodiment 25 provides the curable calcium phosphate composition of anyone of Embodiments 1-24, wherein the composition further comprises aneffervescent agent.

Embodiment 26 provides the curable calcium phosphate composition ofEmbodiment 25, wherein the effervescent agent is about 0.001 wt % toabout 40 wt % of the composition.

Embodiment 27 provides the curable calcium phosphate composition of anyone of Embodiments 25-26, wherein the effervescent agent comprises acombination of at least two compounds.

Embodiment 28 provides the curable calcium phosphate composition of anyone of Embodiments 25-27, wherein the effervescent agent comprises acarbonate compound and a bicarbonate compound which react upon hydrationof said composition to produce carbon dioxide.

Embodiment 29 provides the curable calcium phosphate composition of anyone of Embodiments 1-28, wherein the composition further comprisesdemineralized bone.

Embodiment 30 provides the curable calcium phosphate composition ofEmbodiment 29, wherein the demineralized bone comprises demineralizedbone fibers.

Embodiment 31 provides the curable calcium phosphate composition of anyone of Embodiments 29-30, wherein the demineralized bone is about 0.001wt % to about 40 wt % of the composition.

Embodiment 32 provides a method comprising using the composition of anyone of Embodiments 1-31 or a cured product thereof for treatment of ajoint disorder or condition.

Embodiment 33 provides a cured product of the curable calcium phosphatecomposition of any one of Embodiments 1-31.

Embodiment 34 provides an apparatus comprising a porous structure atleast partially in contact with the curable calcium phosphatecomposition of any one of Embodiments 1-31 or a cured product thereof.

Embodiment 35 provides the apparatus of Embodiment 34, wherein theporous structure comprises a linear olefin polymer or copolymer, anacrylonitrile butadiene styrene (ABS) polymer, an acrylic polymer, acelluloid polymer, a cellulose acetate polymer, a cyclic olegincopolymer (COC), an ethylene-vinyl acetate (EVA) polymer, an ethylenevinyl alcohol (EVOH) polymer, an ethylene n-butyl acetate polymer(EnBA), a fluoroplastic, an ionomer, an acrylic/PVC alloy, a liquidcrystal polymer (LCP), a polyacetal polymer (POM or acetal), apolyacrylate polymer, a polymethylmethaciylate polymer (PMMA), apolyacrylonitrile polymer (PAN or acrylonitrile), a polyamide polymer(PA or nylon), a polyamide-imide polymer (PAI), a polyaryletherketonepolymer (PAEK), a polybutadiene polymer (PBD), a polybutylene polymer(PB), a polybutylene terephthalate polymer (PBT), a polycaprolactonepolymer (PCL), a polychlorotrifluoroethylene polymer (PCTFE), apolytetrafluoroethylene polymer (PTFE), a polyethylene terephthalatepolymer (PET), a polycyclohexylene dimethylene terephthalate polymer(PCT), a polycarbonate polymer (PC), a polyhydroxyalkanoate polymer(PHA), a polyketone polymer (PK), a polyester polymer, a polyethylenepolymer (PE), a polyetheretherketone polymer (PEEK), apolyetherketoneketone polymer (PEKK), a polyetherketone polymer (PEK), apolyetherimide polymer (PEI), a polyethersulfone polymer (PES), apolyethylenechlorinate polymer (PEC), a polyimide polymer (PI), apolylactic acid polymer (PLA), a polymethylpentene polymer (PMP), apolyphenylene oxide polymer (PPO), a polyphenylene sulfide polymer(PPS), a polyphthalamide polymer (PPA), a polypropylene polymer, apolystyrene polymer (PS), a polysulfone polymer (PSU), apolytrimethylene terephthalate polymer (PIT), a polyurethane polymer(PU), a polyvinyl acetate polymer (PVA), a polyvinyl chloride polymer(PVC), a polyvinylidene chloride polymer (PVDC), a polyamideimidepolymer (PAI), a polyarylate polymer, a polyoxymethylene polymer (POM),a styrene-acrylonitrile polymer (SAN), or a combination thereof. Thelinear olefin polymer or copolymer can be ultra high molecular weightpolyethylene (UHMWPE), high-density polyethylene (HDPE), cross-linkedpolyethylene (PEX or XLPE), medium density polyethylene (MDPE), linearlow-density polyethylene (LLDPE), low-density polyethylene (LDPE), verylow-density polyethylene (VLDPE), a copolymer thereof, or a combinationthereof.

Embodiment 36 provides the apparatus of any one of Embodiments 34-35,wherein the porous structure comprises a porous metal structure.

Embodiment 37 provides the apparatus of Embodiment 36, wherein theporous metal structure is about 0.001 wt % to about 100 wt % of theporous structure.

Embodiment 38 provides the apparatus of any one of Embodiments 34-37,wherein the curable calcium phosphate composition or cured productthereof is at least partially within the porous structure.

Embodiment 39 provides the apparatus of any one of Embodiments 36-38,wherein the curable calcium phosphate composition or cured productthereof is at least partially within the porous metal structure.

Embodiment 40 provides the apparatus of any one of Embodiments 36-39,wherein the porous metal structure comprises at least one of tantalum,titanium, niobium, hafnium, tungsten, an alloy thereof, or a combinationthereof.

Embodiment 41 provides the apparatus of any one of Embodiments 36-40,wherein the porous metal structure comprises tantalum.

Embodiment 42 provides the apparatus of any one of Embodiments 36-41,wherein the porous metal structure comprises

a porous substrate comprising a plurality of ligaments that define poresof the porous substrate; and

a biocompatible metal coating on the plurality of ligaments of theporous substrate.

Embodiment 43 provides the apparatus of Embodiment 42, wherein theporous substrate comprises a foam having lower density than thebiocompatible metal coating thereon.

Embodiment 44 provides the apparatus of any one of Embodiments 42-43,wherein the porous substrate comprises reticulated vitreous carbon foam.

Embodiment 45 provides the apparatus of any one of Embodiments 42-44,wherein the biocompatible metal comprises tantalum, titanium, niobium,hafnium, tungsten, an alloy thereof, or a combination thereof

Embodiment 46 provides the apparatus of any one of Embodiments 42-45,wherein the biocompatible metal comprises tantalum.

Embodiment 47 provides the apparatus of any one of Embodiments 42-46,wherein the relative density of the porous metal structure is about 12%to about 50%, the relative density being a percentage obtained bydividing an actual density of the porous metal structure by atheoretical density of the biocompatible metal of the coating.

Embodiment 48 provides the apparatus of any one of Embodiments 36-47,wherein the specific compressive strength of the porous metal structureis at least 24,000 psi.

Embodiment 49 provides the apparatus of any one of Embodiments 34-48,wherein the porous structure comprises a prosthetic implant forimplantation in a hip, knee, ankle, shoulder, spine, jaw, or elbow.

Embodiment 50 provides the apparatus of any one of Embodiments 34-49,wherein the porous structure comprises a prosthetic acetabularcomponent, a prosthetic proximal femoral component, a prosthetic distalfemoral component, a prosthetic tibial component, a prosthetic humeralcomponent, a prosthetic dental component, a prosthetic spinal component,or a combination thereof.

Embodiment 51 provides the apparatus of any one of Embodiments 34-50,wherein the porous structure comprises an acetabular cup, a tibial cone,a glenoid implant, or a distal tibia-talus fusion body.

Embodiment 52 provides the apparatus of any one of Embodiments 36-51,wherein the porous metal structure comprises

a porous substrate comprising a plurality of ligaments that define poresof the porous substrate, the porous substrate comprising reticulatedvitreous carbon foam; and

a biocompatible metal coating on the plurality of ligaments of theporous substrate, the biocompatible metal coating comprising tantalummetal.

Embodiment 53 provides a method comprising using the apparatus of anyone of Embodiments 34-52 for treatment of a joint disorder or condition.

Embodiment 54 provides a method of forming the apparatus of any one ofEmbodiments 34-53, the method comprising:

placing the curable calcium phosphate composition at least partially incontact with the porous structure, to form the apparatus of any one ofEmbodiments 34-53.

Embodiment 55 provides the method of Embodiment 54, wherein the placingcomprises placing the curable calcium phosphate composition into theporous structure, around the porous structure, or a combination thereof.

Embodiment 56 provides the method of any one of Embodiments 54-55,wherein the method is performed in vivo.

Embodiment 57 provides the method of Embodiment 56, further comprisingimplanting the porous structure in a subject prior to placing thecurable calcium phosphate composition at least partially in contact withthe porous structure.

Embodiment 58 provides the method of any one of Embodiments 54-57,wherein the placing of the curable calcium phosphate composition incontact with the porous structure is performed outside the body.

Embodiment 59 provides the method of Embodiment 58, further comprisingimplanting the porous structure in a subject after placing the curablecalcium phosphate composition at least partially in contact with theporous structure.

Embodiment 60 provides the method of any one of Embodiments 54-59,wherein the method comprises primary or revision surgery of a hipimplant, a leg implant, a shoulder implant, a spine implant, a jawimplant, or an ankle implant.

Embodiment 61 provides the method of any one of Embodiments 54-60,wherein the method comprises treatment of osteolytic lesions.

Embodiment 62 provides the composition, apparatus, or method of any oneor any combination of Embodiments 1-61 optionally configured such thatall elements or options recited are available to use or select from.

What is claimed is:
 1. A curable calcium phosphate composition or a cured product thereof, the curable calcium phosphate composition comprising: calcium phosphate; a perfusion modifier, wherein the perfusion modifier is 0.5 wt % to 5 wt % of the curable calcium phosphate composition, wherein the perfusion modifier is methylcellulose, carboxymethylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, a salt thereof, or a combination thereof; and a physiologically acceptable fluid.
 2. The curable calcium phosphate composition or cured product thereof of claim 1, wherein the physiologically acceptable fluid comprises water, saline, phosphate buffer, biological fluid, or a combination thereof, and the biological fluid comprises blood, a blood component, a blood product, milk, urine, saliva, seminal fluid, vaginal fluid, synovial fluid, lymph fluid, amniotic fluid, the fluid within a yolk sac of an egg, chorion of an egg, allantois of an egg, sweat, tears, or a combination thereof.
 3. The curable calcium phosphate composition or cured product thereof of claim 1, wherein the calcium phosphate is about 40 wt % to about 70 wt % of the curable calcium phosphate composition.
 4. The curable calcium phosphate composition or cured product thereof of claim 1, wherein the calcium phosphate comprises amorphous calcium phosphate, poorly crystalline calcium phosphate, hydroxyapatite, carbonated apatite, monocalcium phosphate, calcium metaphosphate, heptacalcium phosphate, dicalcium phosphate dihydrate, tetracalcium phosphate, octacalcium phosphate, calcium pyrophosphate, tricalcium phosphate, or a combination thereof.
 5. The curable calcium phosphate composition or cured product thereof of claim 1, wherein the calcium phosphate comprises amorphous calcium phosphate and dicalcium phosphate dihydrate.
 6. The curable calcium phosphate composition or cured product thereof of claim 1, wherein the curable calcium phosphate composition further comprises a polymer.
 7. The curable calcium phosphate composition or cured product thereof of claim 1, wherein the curable calcium phosphate composition further comprises a polysaccharide, a nucleic acid, a carbohydrate, a protein, a polypeptide, a poly(α-hydroxy acid), a poly(lactone), a poly(amino acid), a poly(anhydride), a poly(orthoester), a poly(anhydride-co-imide), a poly(orthocarbonate), a poly(α-hydroxy alkanoate), a poly(dioxanone), a poly(phosphoester), sodium alginate, alginic acid, arabic gum, guar gum, xantham gum, gelatin, chitin, chitosan, chitosan acetate, chitosan lactate, chondroitin sulfate, N,O-carboxymethyl chitosan, a dextran, fibrin glue, glycerol, hyaluronic acid, sodium hyaluronate, a cellulose, a glucosamine, a proteoglycan, a starch, lactic acid, a poly(ethylene oxide-co-propylene oxide), sodium glycerophosphate, collagen, glycogen, a keratin, silk, poly(L-lactide) (PLLA), poly(D,L-lactide) (PDLLA), polyglycolide (PGA), poly(lactide-co-glycolide) (PLGA), poly(L-lactide-co-D, L-lactide), poly(D,L-lactide-co-trimethylene carbonate), polyhydroxybutyrate (PHB), poly(ϵ-caprolactone), poly(δ-valerolactone), poly(δ-butyrolactone), poly(caprolactone), polyacrylic acid, polycarboxylic acid, poly(allylamine hydrochloride), poly(diallyldimethylammonium chloride), poly(ethyleneimine), polypropylene fumarate, polyvinyl alcohol, polyvinylpyrrolidone, polyethylene, polymethylmethacrylate, carbon fibers, poly(ethylene glycol), poly(ethylene oxide), poly(vinyl alcohol), poly(vinylpyrrolidone), poly(ethyloxazoline), poly(ethylene oxide)-co-poly(propylene oxide) block copolymers, poly(ethylene terephthalate)polyamide, copolymers thereof, or a combination thereof.
 8. The curable calcium phosphate composition or cured product thereof of claim 1, wherein the perfusion modifier is carboxymethylcellulose, a salt thereof, or a combination thereof.
 9. The curable calcium phosphate composition or cured product thereof of claim 1, wherein the perfusion modifier is a lyophilized perfusion modifier.
 10. The curable calcium phosphate composition or cured product thereof of claim 1, wherein the curable calcium phosphate composition further comprises a biologically active modifier that is at least one of an antibody, an antibiotic, a polynucleotide, a polypeptide, a protein, an anti-cancer modifier, a growth factor, a vaccine, or a combination thereof, wherein the biologically active modifier is about 0.001 wt % to about 40 wt % of the curable calcium phosphate composition.
 11. The curable calcium phosphate composition or cured product thereof of claim 10, wherein the biologically active modifier is about 0.001 wt % to about 10 wt % of the curable calcium phosphate composition.
 12. The curable calcium phosphate composition or cured product thereof of claim 1, wherein the curable calcium phosphate composition further comprises a binder that is about 0.001 wt % to about 20 wt % of the curable calcium phosphate composition.
 13. The curable calcium phosphate composition or cured product thereof of claim 12, wherein the binder is about 0.001 wt % to about 5 wt % of the curable calcium phosphate composition.
 14. The curable calcium phosphate composition or cured product thereof of claim 12, wherein the binder is at least one of a) a polysaccharide, a nucleic acid, a carbohydrate, a protein, a polypeptide, a poly(α-hydroxy acids), a poly(lactone), a poly(amino acid), a poly(anhydride), a poly(orthoester), a poly(anhydride-co-imide), a poly(orthocarbonate), a poly(α-hydroxy alkanoate), a poly(dioxanone), a poly(phosphoester), poly(L-lactide) (PLEA), poly(D,L-lactide) (PDLEA), polyglycolide (PGA), poly(lactide-co-glycolide (PLEA), poly(L-lactide-co-D, L-lactide), poly(D,L-lactide-co-trimethylene carbonate), polyhydroxybutyrate (PHB), poly(ϵ-caprolactone), poly(δ-valerolactone), poly(γ-butyrolactone), poly(caprolactone), polyacrylic acid, polycarboxylic acid, poly(allylamine hydrochloride), poly(diallyldimethylammonium chloride), poly(ethyleneimine), polypropylene fumarate, polyvinyl alcohol, polyvinylpyrrolidone, a polyethylene, polymethylmethacrylate, a carbon fiber, poly(ethylene glycol), poly(ethylene oxide), poly(vinyl alcohol), poly(vinylpyrrolidone), poly(ethyloxazoline), a poly(ethylene oxide)-co-poly(propylene oxide) block copolymer, poly(ethylene terephthalate)polyamide, and copolymers thereof; b) a homo- or co-polymer having one or more monomers selected from the group consisting of acrolein potassium, (meth)acrylamides, (meth)acrylic acid and salts thereof, (meth)acrylates, acrylonitrile, ethylene, ethylene glycol, ethyleneimine, ethyleneoxide, styrene sulfonate, vinyl acetate, vinyl alcohol, vinyl chloride, and vinylpyrrolidone); c) a polyphenol complexing agent selected from a gallotannin, a ellagitannin, a taragallotannin, a caffetannin, a proanthocyanidin, catechin, epi catechin, chlorogenic acid, and arbutin; and d) an agent selected from alginic acid, arabic gum, guar gum, xanthan gum, gelatin, chitin, chitosan, chitosan acetate, chitosan lactate, chondroitin sulfate, N,O-carboxymethyl chitosan, a dextran, fibrin glue, glycerol, hyaluronic acid, sodium hyaluronate, a cellulose, a glucosamine, a proteoglycan, a starch, lactic acid, a poly(ethylene oxide-co-propylene oxide), sodium glycerophosphate, collagen, glycogen, a keratin, and silk.
 15. The curable calcium phosphate composition or cured product thereof of claim 1, wherein the curable calcium phosphate composition further comprises an effervescent agent that is about 0.001 wt % to about 40 wt % of the curable calcium phosphate composition.
 16. The curable calcium phosphate composition or cured product thereof of claim 15, wherein the effervescent agent is 1 wt % to 10 wt % of the curable calcium phosphate composition.
 17. The curable calcium phosphate composition or cured product thereof of claim 15, wherein the effervescent agent comprises a carbonate compound and a bicarbonate compound which react upon hydration of said composition to produce carbon dioxide.
 18. The curable calcium phosphate composition or cured product thereof of claim 1, wherein the curable calcium phosphate composition further comprises demineralized bone that is about 0.001 wt % to about 40 wt % of the curable calcium phosphate composition.
 19. The curable calcium phosphate composition or cured product thereof of claim 1, comprising the cured product of the calcium phosphate composition.
 20. A method comprising treating a joint disorder or condition with the curable calcium phosphate composition of cured product thereof of claim
 1. 